4-Substituted-2-arylimidazoles

ABSTRACT

4-Substituted-2-arylimidazoles, wherein the 4-substituent is sulfur containing, are disclosed. The compounds have pharmaceutical activity.

This is a division of application Ser. No. 773,248, filed Mar. 1, 1977now U.S. Pat. No. 4,110,456.

BACKGROUND OF THE INVENTION

The present invention is directed to 4-sulfur containingsubstituted-2-arylimidazoles having antihypertensive and/or xanthineoxidase inhibiting activity.

4-Non-sulfur containing substituted 2-aryl (or alkyl)imidazoles aredisclosed in U.S. Pat. No. 3,691,178, issued Sept. 12, 1972. Thesecompounds have xanthine oxidase inhibiting activity. U.S. Pat. No.3,786,061 discloses 4-trifluoromethyl-2-arylimidazoles havingpharmaceutical activity as antihypertensives and xanthine oxidaseinhibitors.

The compounds of the present invention are 2-arylimidazoles having asulfur bearing substitutent in the 4-position -- and havingantihypertensive and/or xanthine oxidase inhibiting activity.

SUMMARY OF THE INVENTION

4-Sulfur containing substituted-2-arylimidazoles, their preparation andpharmaceutical use.

DESCRIPTION OF PREFERRED EMBODIMENTS

A preferred embodiment of the present invention is compounds having theformula ##STR1## and pharmaceutically acceptable salts thereof wherein

R₁ is selected from the group consisting of monohalo (e.g. Cl, Br, I orF)-phenyl, dihalo¹ (e.g. Cl or Br)-phenyl and pyridyl (e.g. 3-pyridyl,4-pyridyl),

halo is Cl, Br, I or F

R₂ is selected from the group consisting of C₁ -C₅ alkyl-S--, C₁ -C₅alkyl-SO--, C₁ -C₅ alkyl-SO₂ -- and R₃ R₄ N--SO₂ --, and

R₃ and R₄ are independently selected from H, C₁ -C₅ alkyl and hydroxysubstituted C₂ -C₅ alkyl,

excluding compounds where R₁ is 4-chlorophenyl and R₂ is C₁ -C₅alkyl-SO-- or C₁ -C₅ alkyl-SO₂ --.

These compounds are 2,4(5)disubstituted imidazoles.

The alkyl moiety in the R₂ groups defined above includes branched andstraight chain alkyl groups such as CH₃ --, t-butyl, n-pentyl and thelike. The hydroxy substituted C₂ -C₅ alkyl groups are also branched andstraight chain alkyls having 1-2 hydroxy groups -- the monohydroxystraight chain alkyls are preferred e.g. --CH₂ --CHOH--CH₃ and --(CH₂)₅--OH.

The pharmaceutically acceptable salts include metal salts e.g. Na, K,the alkaline earth metals, quaternary salts and acid addition salts ofthe formula I compounds. The metal salts can be prepared by conventionaltreatment of the Formula I compound with suitable base, e.g. NaOH, KOH,CaO etc. The quaternary salts can be prepared where the R₁ group ispyridyl by conventional treatment of the Formula I compound with analkyl iodide such as methyl iodide, ethyl iodide and the like. The acidaddition salts can be prepared by conventionally treating the Formula Icompound where the R₁ group is pyridyl with a suitable inorganic ororganic acid. Suitable inorganic acids are the hydrohalides e.g. HCl,HI, HBr, sulfuric acid, phosphoric acid and the like. Suitable organicacids are exemplified by C₂ -C₂₄ carboxylic acids such as acetic acid,tetracosanic acid, oleic acid, 2-ethylhexoic acid, maleic acid, pamoicacid, lactic acid, citric acid, succinic acid, malic acid,trimethylacetic acid, oxalic acid, fumaric acid, cyclohexyl carboxylicacid, lauric acid and the like -- and non-carboxylic acids such asisethionic acid.

A preferred class of compounds are those having the formula ##STR2##where halo¹ preferably are in the 3,4 position and are both chloro orbromo -- and more preferably chloro. In a most preferred Formula IIcompound, halo¹ substitution is 3,4-dichloro and R₂ ' is H₂ NSO₂ --.

A representative compound of Formula II shows xanthine oxidaseinhibiting activity when tested in vitro.

Another preferred embodiment is a compound having the formula ##STR3##halo, in Formula III, is preferably in the 4-position, more preferably4-bromo or 4-chloro and most preferably 4-chloro. R₂ " is preferably C₁-C₅ alkyl-S-- or R₃ R₄ N--SO₂ -- where R₃ and R₄ are independentlyselected from hydrogen, C₁ -C₅ alkyl and hydroxy-C₂ -C₅ alkyl.

Compounds of Formula III exhibit random activity as xanthine oxidase(x.o.) inhibitors and antihypertensive agents. The x.o. inhibitingactivity is determined in an in vitro test -- the antihypertensiveactivity is determined by administration of the compound to aspontaneously hypertensive (SH) rat. The antihypertensive and x.o.inhibiting activities of representative Formula III compounds, wheretested, are tabulated below.

                  TABLE I                                                         ______________________________________                                        Antihypertensive and X.O. Inhibiting Activity                                 for                                                                           Compounds of Formula                                                           ##STR4##                                                                                                    X.O.                                                             Antihypertensive                                                                           Inhibiting                                     R.sub.2 '  Substituent                                                                          Activity     Activity                                       ______________________________________                                        (CH.sub.3).sub.2 CHS                                                                            yes          no                                             H.sub.3 CS        yes          yes                                            (H.sub.3 C).sub.2 NSO.sub.2                                                                     no           yes                                            H.sub.2 NSO.sub.2 yes          no                                             HOCH.sub.2CH.sub.2NHSO.sub.2                                                                    yes          --                                             ______________________________________                                    

Another preferred embodiment is a compound having the formula ##STR5##In preferred compounds of Formula IV, the pyridyl group is 3-pyridyl andR₂ is R₃ 'R₄ 'N--SO₂ --where R₃ ' and R₄ ' are independently selectedfrom hydrogen and C₁ -C₅ alkyl. Compounds of Formula IV have exhibitedantihypertensive activity in the SH rat. The compounds of Formula IV mayalso have x.o. inhibiting activity.

Another preferred embodiment is compounds having Formula IA. A morepreferred embodiment is compounds having the formula ##STR6## whereinhalo is Cl, Br, I or F and R₃ and R₄ is as defined above. Compounds ofFormula IV A where halo is Cl or Br are more preferred. Hydrogen is apreferred definition of R₃ and R₄.

Compounds of Formula IA or IV A are xanthine oxidase inhibitors and/orantihypertensives.

The xanthine oxidase inhibiting activity of the present compoundsindicates that they will be useful for treating gout and hyperuricemiain human patients. Administration of the compounds may be oral orparenteral, using appropriate dosage forms e.g. tablets, capsules,sterile solutions, elixirs etc. Daily dosage for this utility may bevaried, ranging from about 20 mg to about 1.5 gm and preferably fromabout 100 to about 800 mg.

The antihypertensive activity exhibited by the present compoundsindicates that they will be useful for treating hypertension (loweringblood pressure) in human patients. Administration of the compounds maybe oral or parenteral e.g. intravenous, intraperitoneal, intramuscular,etc., using appropriate dosage forms, e.g. tablets, capsules, sterilesolutions, emulsions etc. Daily dosage for the utility may be variedranging from about 10 mg to about 1500 mg, preferably from about 100 mgto about 1000 mg.

The R₃ R₄ N--SO₂ -- substituted compounds of Formula I are prepared bythe general route illustrated by the following reactions ##STR7## WhereR₁ is monohalophenyl, e.g. 4-bromophenyl, 4-iodophenyl, 2-fluorophenyl,3-chlorophenyl and the like, chlorosulfonation occurs at the 4(5)imidazole position when the chlorosulfonation is carried out at or belowabout 100° C. When the chlorosulfonation temperature is higher [aboveabout 100° C. to the reflux temperature of the chlorosulfonating agent(ClSO₃ H/SOCl₂)], chlorosulfonation of the phenyl ring also occurs.Treatment of this dichlorosulfonated product with amines or ammoniayields the compounds of Formula IA, are illustrated by the followingequations: ##STR8## The amination reaction (2) can be carried out withexcess R₃ R₄ NH as solvent, or with a solution of R₃ R₄ NH. Solvents,such as water, ether, chloroform, methylene chloride, can be used.Amination temperatures may vary over a wide range. A convenienttemperature range for primary or secondary amines or R₃ R₄ NH solutionsis 0° C. to 100° C. When dichlorosulfonyl products such as (e) areemployed, the R₃ and R₄ substituents present in the R₃ R₄ NH reactantappear as substituents in both sulfamoyl groups. Compounds of formula(d) may be conveniently prepared by reacting a 1,2 diketone with ammoniaand the appropriate halobenzaldehyde [Davidson et al, J. Org. Chem., 2,319, (1937)]. The chlorosulfonation (1) is carried out under conditionsessentially as those described in Journal or Organic Chemistry 25, 965(1960).

The C₁ -C₅ alkyl-S--, C₁ -C₅ alkyl-SO-- and C₁ -C₅ alkyl-SO₂ --substituted compounds of Formula I are prepared according to theprocedure illustrated by the following reaction equation. ##STR9## Thereduction (x) was carried out according to the procedure described inJournal of Organic Chemistry 24, 289 (1959). The alkylsulfide isprepared by treating the thiol with an alkyl iodide (Y). The sulfide isoxidized (Z) to prepare the sulfinyl or sulfonyl analog.

The following examples illustrate preparation of representativeintermediates and compounds of the present invention. All temperaturesare in ° C. unless otherwise indicated.

EXAMPLE 1 Preparation of 2-(4-chlorophenyl)-4(5) sulfamoylimidazole

A. 2-(4-chlorophenyl)imidazole (6 g., 0.034 mole) was added portionwiseat room temperature with stirring to chlorosulfonic acid (30 ml.). Themixture was heated 2 hours at 100° and cooled to room temperature.Thionyl chloride (3 g.) was added and the mixture again heated for 2hours at 100°. After cooling to room temperature the mixture was addedcautiously to ice and water. A semi-solid separated and was extractedwith ether. The ether layer was dried and concentrated to yield2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g., 0.005 mole).

B. 2-(4-Chlorophenyl)-4-chlorosulfonylimidazole (1 g., 0.0036 mole) wasadded portionwise with stirring to liquid ammonia (100 ml.). The ammoniawas allowed to evaporate yielding a solid which was triturated withether. The insoluble solid was removed by filtration and washed withwater. The ether solution was concentrated to a solid and the twoportions of solid were combined and recrystallized from acetonitrile toyield 0.36 g. of 2-(4-chlorophenyl)-4(5)-sulfamoylimidazole, m.p.242°-245°.

EXAMPLE 2 Preparation of2-(4-chlorophenyl)-4(5)-dimethylsulfamoylimidazole

To a solution of 2-(4-chlorophenyl)-4(5)-chlorosulfonyl imidazole (1.3g., 0.005 mole) in dioxane (15 ml.) was added dropwise with stirring atroom temperature a 25% aqueous solution of dimethylamine (2 g.). After 1hour the reaction mixture was concentrated under reduced pressure (25mm); water (10 ml.) was added and the solid filtered. Afterrecrystallization from acetonitrile 0.55 g. of2-(4-chlorophenyl)-4(5)-dimethylsulfamoylimidazole melting at 211°-213°was obtained.

EXAMPLE 3 Preparation of 2-(4-chlorophenyl)-4-methylsulfamoylimidazole

Substituting aqueous methylamine for the dimethylamine in Example 32-(4-chlorophenyl)-4-methyl-sulfamoylimidazole, melting at 246°-248°,was obtained (4.4% yield).

EXAMPLE 4 Preparation of 2-(3,4-dichlorophenyl)-4(5)-sulfamoylimidazole

2-(3,4-Dichlorophenyl)imidazole (3.0 g., 0.014 mole) was added withstirring to chlorosulfonic acid (15 ml.). The mixture was heated 2 hoursat 150°, cooled to room temperature and thionyl chloride (1.5 g.) wasadded. the solution was heated an additional 2 hours at 150°,cooled andadded cautiously to ice and water. The resulting solid was filtered,washed with water and added to liquid ammonia (25 ml.). After stirring 2hours, the ammonia was allowed to evaporate and the residuerecrystallized from acetonitrile and then from methanol-water to yield1.5 g. of 2-(3,4-dichlorophenyl)-4(5)-sulfamoylimidazole melting at243°-244.5°.

EXAMPLE 5 Preparation of2-(4-chloro-3-sulfamoylphenyl)-4(5)-sulfamoylimidazole

2-(4-Chlorophenyl)imidazole (3.0 g., 0.017 mole) was added portionwisewith stirring to chlorosulfonic acid (15 ml). The mixture was heated 2hours at 110°, cooled and thionyl chloride (1.5 g.) was added. Thesolution was again heated at 170° for 2 hours. After cooling to roomtemperature, the mixture was cautiously added to ice and water. Theresulting solid was filtered, washed with water and added portionwise toliquid ammonia (50 ml.). After stirring 2 hours the ammonia was allowedto evaporate and the resulting solid recrystallized fromwater-dimethylformamide to yield 1 g. of2-(4-chloro-3-sulfamoylphenyl)-4(5)-sulfamoylimidazole melting, withdecomposition, at 338° C.

EXAMPLE 6 Preparation of 2-(3-pyridyl)-4(5)-methylsulfamoylimidazole

A solution of chlorosulfonic acid (10 ml.) and 2-(3-pyridyl)imidazole(2.0 g., 0.014 mole), was heated at reflux for 7 hours and cooled toroom temperature. Thionyl chloride (1.1 ml.) was added and the solutionwas heated an additional 8 hours at reflux. The excess chlorosulfonicacid was distilled off under reduced pressure (5 mm) and the residuetreated with 40% aqueous methylamine (25 ml.). After standing 17 hoursat room temperature, the solution was concentrated to dryness underreduced pressure (25 mm). The residue was chromatographed on alumina(Brinkmann-activity 2) and eluted with 2% methanol-chloroform to give0.52 g. (16%) of 2-(3-pyridyl)-4(5)-methylsulfamoylimidazole melting at212°-213° after crystallization from methanol-toluene.

Using 28-30% aqueous ammonia in place of the methylamine in the Example6 procedure, 2-(3-pyridyl)-4(5)-sulfamoylimidazole, melting at274°-275°, was obtained (11% yield).

Replacing the aqueous methylamine in the Example 6 procedure with a 25%solution of diethylamino in dioxane,2-(3-pyridyl)-4(5)-diethylsulfamoylimidazole, melting at 150°-152°, wasobtained (9% yield).

EXAMPLE 7 Preparation of 2-(4-chlorophenyl)-4(5)-methylthioimidazole

To a solution of 2-(4-chlorophenyl)-4(5)-chlorosulfonylimidazole (1.7g., 0.00615 mole) in acetic acid (35 ml.) was added a solution ofstannous chloride dihydrate (7 g., 0.031 mole) in concentratedhydrochloric acid (6 ml.) with stirring at 65°. After heating at 65°-75°for 1/2 hour, the reaction mixture was cooled and poured into water (125ml.) containing concentrated hydrochloric acid (6 ml.). A yellow solid,2-(4-chlorophenyl)-4-mercaptoimidazole was filtered off, washed withwater and suspended in water (25 ml.). To the stirred suspension undernitrogen was added a 20% aqueous solution of sodium hydroxide (5 ml.);methyl iodide (3.4 g., 0.024 mole) was then added. After stirring 1.5hours, 2-(4-chlorophenyl)-4(5)-methylthioimidazole was removed byfiltration, recrystallized from benzene and sublimed at 160° and 0.2 mmto yield 0.5 g. (58%), m.p. 170°-172° .

Using isopropyl iodide in place of the methyl iodide, and K₂ CO₃ indimethylformamide (DMF) in place of the aqueous sodium hydroxide inExample 7, 2-(4-chlorophenyl)-4(5)-isopropylthioimidazole, melting at195°-197°, was obtained.

EXAMPLE 8 Preparation of 2-(4-chlorophenyl)-4(5)-methylsulfinylimidazole

To 700 mg. (0.003 mole) of 2-(4-chlorophenyl)-4(5)-methylthioimidazolein acetic acid (5 ml.) was added with stirring at room temperature 30%hydrogen peroxide (5 drops). Two additional portions of 30% hydrogenperoxide (5 drops) were added after 2 and 4 hours. Two hours after thelast addition of hydrogen peroxide, water (10 ml.) was added and thesolution was neutralized with 10% aqueous sodium hydroxide solution. Anoil separated, solidified and was filtered. After recrystallization fromhexane, 500 mg. (69.2%) of2-(4-chlorophenyl)-4(5)methylsulfinylimidazole melting at 176° C. wasobtained.

2-(4-Chlorophenyl)-4(5)-isopropylsulfinylimidazole, melting at173°-175°, was obtained according to the procedure of Example 8 using2-(4-chlorophenyl)-4(5)-isopropylthioimidazole in place of the2-(4-chlorophenyl)-4(5)-methylthioimidazole, and carrying the reactionout for 2 hours at 100° instead of 6 hours at room temperature.

EXAMPLE 9 Preparation of 2-(4-chlorophenyl)-4(5)-methylsulfonylimidazole

To 2-(4-chlorophenyl)-4(5)-methylthioimidazole (0.7 g., 0.003 mole) inacetic acid (7 ml.) was added at room temperature 30% hydrogen peroxide(15 drops) and the mixture heated 1.5 hours at 100°. A second portion of30% hydrogen peroxide (15 drops) was added and heating continued for 1.5hours. The solution was neutralized with 10% aqueous sodium hydroxidesolution and 2-(4-chlorophenyl)-4(5)-methylsulfonylimidazole separated,was filtered and recrystallized from acetonitrile-water to yield 300 mg.(37.7%), melting at 210°-211°.

EXAMPLE 10 Preparation of2-(4-chlorophenyl)-4-(2-hydroxyethylsulfamoyl)imidazole

To a solution of 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g0.005 m) in dioxane (15 ml) was added ethanolamine (0.61 g 0.01 ml).After 15 minutes the dioxane was removed under reduced pressure (20 mm)to yield a gum. The gum was slurried with water to yield a solid. Thesolid was filtered and recrystallized from acetonitrile to give 400 mgof 2-(4-chlorophenyl)-4-(2-hydroxyethylsulfamoyl)imidazolemelting at210°-212°. (20% yield).

Claims to the invention follow.

What is claimed is:
 1. A compound having the formula ##STR10## whereinR₁ is selected from the group consisting of mono chloro, bromo, iodo orfluoro- phenyl and dichloro- or dibromo-phenyl,halo is chloro, bromo,iodo or fluoro; R₃ is selected from the group consisting of C₁ -C₅alkyl-S--, C₁ -C₅ alkyl-SO--, C₁ -C₅ alkyl-SO₂ -- and R₃ R₄ N--SO₂ --,and R₂ and R₄ are independently selected from H, C₁ -C₅ alkyl andhydroxy substituted C₂ -C₅ alkyl,such that when R₁ is 4-chlorophenyl, R₂is other than C₁ -C₅ alkyl-SO-- or C₁ -C₅ alkyl-SO₂ --.
 2. A compound ofclaim 1 having formula I wherein R₁ is 3,4-dichloro or3,4-dibromophenyl.
 3. A compound of claim 2 wherein R₁ is3,4-dichlorophenyl.
 4. A compound of claim 3 wherein R₂ is H₂ NSO₂ --.5. A compound of claim 1 having formula I wherein R₁ is 4-halophenyl. 6.A compound of claim 5 wherein R₁ is 4-chlorophenyl.
 7. A compound ofclaim 6 wherein R₂ is (CH₃)₂ CH--S--, CH₃ --S--, H₃ C--NHSO₂ --, (CH₃)₂N--SO₂ --, H₂ NSO₂ and HO--CH₂ --CH₂ --NH--SO₂ --.
 8. A compound ofclaim 1 having the formula: ##STR11##
 9. A compound of claim 8 whereinhalo is chloro or bromo.
 10. A compound of claim 9 wherein R₃ and R₄ areeach H.
 11. A compound of claim 10 wherein halo is chloro.
 12. Acomposition for treating hypertension containing an effective amount ofa compound selected from the group consistingof2-(4-chlorophenyl)-4-methylthioimidazole,2-(4-chlorophenyl)-4-isopropylthioimidazole,2-(4-chlorophenyl)-4-sulfamoylimidazole and2-(4-chlorophenyl)-4-(2-hydroxyethylsulfamoyl)imidazole and an inertpharmaceutical carrier.
 13. A composition for inhibiting xanthineoxidase containing an effective amount of a compound selected from thegroup consisting of 2-(3,4-dichlorophenyl)-4-sulfamoylimidazole,2-(4-chlorophenyl)-4-methylthioimidazole,2-(4-chlorophenyl)-4-methylsulfamoylimidazole and2-(4-chlorophenyl)-4-dimethylsulfamoylimidazole and an inertpharmaceutical carrier.
 14. A composition for treating hypertensioncontaining an effective amount of a compound of claim 1 having formulaIA and an inert pharmaceutical carrier.
 15. A composition for inhibitingxanthine oxidase containing an effective amount of a compound of claim 1having formula IA and an inert pharmaceutical carrier.